Background: Sorafenib is widely used for treatment of hepatocellular carcinoma (HCC), but the acquired resistance remains a major obstacle for its application. Thus it is of critical importance to elucidate the molecular mechanisms underlying sorafenib resistance in HCC. This study aimed to determine the roles of long noncoding RNA SNHG16 in sorafenib-resistant HCC cells.
Methods: HCC and matched adjacent normal liver tissue samples were obtained from 103 HCC patients. Sorafenib-resistant HepG2/SOR cell line was established from its parental HepG2 cells by exposure to increasing concentrations of sorafenib. SNHG16 and miR-140-5p expression levels in tissue samples and cells were detected by RT-qPCR analysis. The sensitivity of cells to sorafenib in vitro was evaluated by MTT assay, and the sensitivity of HepG2/SOR cells to sorafenib in vivo was estimated using the nude mouse-based xenograft model. The potential binding relation between SNHG16 and miR-140-5p was validated by dual luciferase reporter assay and biotinylated RNA pull-down assay.
Results: The results showed that SNHG16 expression was remarkably increased in HCC tissues and cell lines, and its high expression was closely associated with aggressive clinicopathological features and poor prognosis of HCC patients. Further experiments showed that SNHG16 is upregulated in HepG2/SOR cells, whereas knockdown of SNHG16 increases the sensitivity of HepG2/SOR cells to sorafenib in vitro and in vivo. Further mechanistic study identified that SNHG16 functions as an endogenous sponge for miR-140-5p in HepG2 cells, and in HCC tissues, the expression of miR-140-5p is negatively correlated with SNHG16 expression. Moreover, miR-140-5p overexpression also increases the sensitivity of HepG2/SOR cells to sorafenib, and the effects of SNHG16 knockdown on sorafenib resistance could be blocked by miR-140-5p inhibitor.
Conclusion: Collectively, our findings demonstrated that knockdown of SNHG16 attenuated sorafenib resistance in HCC through sponging miR-140-5p, indicating that SNHG16 might be as a promising therapeutic target to boost the effectiveness of chemotherapy for HCC patients.
Keywords: long noncoding RNA, SNHG16, hepatocellular carcinoma, sorafenib resistance, miR-140-5p